Abstract
FK506-binding proteins (FKBPs) alter the conformation of proteins via cis-trans isomerization of prolyl-peptide bonds. While this activity can be demonstrated in vitro, the intractability of detecting prolyl isomerization events in cells has limited our understanding of the biological processes regulated by FKBPs. Here we report that FKBP25 is an active participant in the repair of DNA double-strand breaks (DSBs). FKBP25 influences DSB repair pathway choice by promoting homologous recombination (HR) and suppressing single-strand annealing (SSA). Consistent with this observation, cells depleted of FKBP25 form fewer Rad51 repair foci in response to etoposide and ionizing radiation, and they are reliant on the SSA repair factor Rad52 for viability. We find that FKBP25’s catalytic activity is required for promoting DNA repair, which is the first description of a biological function for this enzyme activity. Consistent with the importance of the FKBP catalytic site in HR, rapamycin treatment also impairs homologous recombination, and this effect is at least in part independent of mTor. Taken together these results identify FKBP25 as a component of the DNA DSB repair pathway.
Highlights
FK506-binding proteins (FKBPs) are enzymes that catalyze the cis-trans isomerization of prolylpeptide bonds to regulate substrate protein structure and function
It has recently become apparent that tight control over the chromatin environment surrounding double-strand breaks (DSBs) is required for repair as during the DNA Damage Response (DDR) there is an initial expansion of chromatin followed by a phase of chromatin condensation (Burgess et al 2014; Khurana et al 2014; Li et al 2014). These results suggest that FKBP25 displacement at sites of DSB may play a role in the reorganization of the chromatin environment to promote repair by homologous recombination
We expand on prior observations that FKBP25 physically interacts with a number of DSB repair factors by demonstrating that this prolyl isomerase promotes homologous recombination in a https://mc06.manuscriptcentral.com/bcb-pubs mechanism that likely involves catalytic activity
Summary
FK506-binding proteins (FKBPs) are enzymes that catalyze the cis-trans isomerization of prolylpeptide bonds to regulate substrate protein structure and function. FKBP25 is cytoplasmic/nuclear enzyme that directly binds both DNA (Prakash et al 2016) and doublestranded RNA (Dilworth et al 2017). We previously used affinity purifications and BioID proximity labeling to identify FKBP25-associated proteins; these include ribosomal proteins, RNA-binding proteins, elements of the cytoskeleton and chromatin-associated factors (Dilworth et al 2017; Gudavicius et al 2014). Included in these interactors were a number of regulators of the DNA damage repair process, including: histone H1, Ku86, Ku70, MDC1, DNA-dependent protein kinase
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